Incidence, hospitalization, and mortality in children aged 5 years and younger with respiratory syncytial virus‐related diseases: A systematic review and meta‐analysis

Abstract Objectives Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in young children. We aimed to analyze the factors affecting the estimation of RSV‐related disease burden, and to provide evidence to help establish a surveillance system. Methods We searched the English‐ and Chinese‐language databases for articles published between January 1, 2010 and June 2, 2022. The quality of the included articles was assessed using the Agency for Healthcare Research and Quality scale. Random‐effects models were used for data synthesis and subgroup analyses. This review was registered in the Prospective Register of Systematic Reviews (PROSPERO: CRD42022372972). Results We included 44 studies (149,321,171 participants), all of which were of medium or high quality. The pooled RSV‐related disease incidence, hospitalization rate, in‐hospital mortality, and overall mortality rates in children aged 5 years and younger were 9.0 per 100 children per year (95% confidence interval [CI]: 7.0–11.0), 1.7 per 100 children per year (95% CI: 1.3–2.1), 0.5 per 100 children per year (95% CI: 0.4–0.5), and 0.05 per 100 children per year (95% CI: 0.04–0.06), respectively. Age, economics, surveillance types, case definition, and data source were all recognized as influencing factors. Conclusions A standardized and unified RSV surveillance system is required. Case definition and surveillance types should be fully considered for surveillance of different age groups.


| INTRODUCTION
Respiratory syncytial virus (RSV) is a ubiquitous respiratory virus with a single-stranded negative-sense RNA. 1 RSV is one of the major causes of acute lower respiratory tract infection (ALRI) in children aged under 5 years, with a population attribution fraction of 18.2% (95% confidence interval [CI]: 17.4-19.0%) in developing countries. 2 Further, ALRI is a leading cause of death globally in children under 5 years. 3 Early childhood RSV-related ALRI may be associated with subsequent development of recurrent wheezing and asthma, 4 which may reduce with quality of life, and impose a considerable burden on healthcare utilization. 5 Estimates have been published of the global disease burden of RSV ALRI in children under 5 years of age in 2005, 2015, and 2019. [6][7][8] Factors affecting the RSV disease burden vary according to age, region, type of surveillance, 8 case definition, 9 and the diagnostic tests. 10 Some factors may lead to an underestimation of the burden of RSV-related disease. 11 Moreover, due to heterogeneity among studies, the results of different studies lack comparability. Therefore, it is important to identify the factors that influence estimates of RSV burden in order to develop a standardized RSV surveillance system. 12 In recent years, the epidemiology of RSV has changed owing to the public health and social measures implemented during the coronavirus disease 2019 (COVID-19) pandemic. 13,14 RSV incidence, out-ofseason activity, and health-service demands may increase when these preventive measures are relaxed. 14 The potential effect of  and RSV coinfection is a concern, especially in infants who have not been vaccinated during the COVID-19 pandemic. 14 Considerable progress has been made regarding RSV prevention, including thorough research into maternal vaccination in the antenatal period, and administration of long-acting monoclonal antibodies to infants; 15 thus, exploring key factors for establishing a standardized surveillance system will further provide evidence for the development of the national vaccination program. To achieve these objectives, we performed a systematic literature review and meta-analysis to clarify the RSVrelated disease incidence, hospitalization rate, in-hospital mortality rate, and overall mortality among children aged 5 years and younger.
We aimed to explore factors that may impact RSV-related disease burden estimates and help make suggestions for a standard and feasible surveillance system.
After removing duplicate articles, the titles and/or abstracts were screened by two independent reviewers to meet the following criteria: (1) the included children were aged ≤5 years, who had RSV and were otherwise healthy; (2) the outcome indicators were RSV-related disease incidence, hospitalization rate, in-hospital mortality rate, and overall mortality; (3) the study design was cohort, cross-sectional, case-control, case-cohort, or nested case-control; and (4) the sample size was over 1000. We excluded studies without data on children aged under 5 years or that only reported data on children with comorbidities or underlying conditions, such as Down syndrome, congenital heart disease, and immunodeficiency. Further, we excluded studies that reported proportions, comparison of RSV diagnostic tests, animal research, repeated publications, letters, comments, case reports, case series, editorials, reviews, pure modeling studies or modeling studies for trend estimation, and studies with unavailable full text or those that were published in languages other than Chinese or English. The full texts of included studies were reviewed by two independent reviewers to assess their eligibility based on the inclusion and exclusion criteria. A third reviewer was consulted to reach consensus if the two reviewers' assessments did not concur.

| Data extraction and quality assessment
Data on the eligible studies were extracted by two researchers independently and simultaneously, and then exchanged for checking to prevent data errors. When data were inconsistent among reviewers, they discussed and reassessed the article until they reached agreement. The data extraction checklist included the name of the first author, survey period, region or country where the study was conducted, race, study design (active or passive surveillance), data source (national database or hospital database), case definition (extended acute respiratory illness [ARI] or influenza-like illness [ILI], Table S2), sample collection or detection method, sample size, age group, sex, quality score, and main outcomes that included RSV-related disease incidence, hospitalization rate, in-hospital mortality rate, and overall mortality (Tables S3-S6).
Two independent reviewers used the Agency for Healthcare Research and Quality assessment tool (Table S7) to evaluate the risk of bias for cross-sectional studies. 17

| Data synthesis and analysis
Pooled estimates of one-group meta-analyses were used to estimate the synthesis effect size and 95% CIs for RSV-related disease incidence, hospitalization rate, in-hospital mortality rate, and overall mortality in children aged 0-5 years. Subgroup analyses were performed to explore potential determinants affecting the RSV-related disease burden, such as age, income level (according to the 2021 World Bank classification), surveillance type (active or passive surveillance), case definition (extended ARI or ILI), and data source. Table S2 contains detailed definitions and criteria for subgroup division. The Cochrane Q test and I 2 were used to assess the heterogeneity of the studies, with <25%, 25%-50%, and >50% indicating low-, moderate-, and high-level heterogeneity, respectively. As the heterogeneity of all pooled results was greater than 50%, a randomeffects model was used for the analysis, and the pooled effect size was weighted by the random-effects model. Forest plots were used to present the data. Sensitivity analyses were performed by omitting each study individually to determine whether any included studies had a marked impact on the results and to examine the robustness of the overall effect. Potential publication bias was evaluated graphically and quantitatively using funnel plots and Egger's test, respectively. ( p-Values <0.05 indicated significant publication bias.) All statistical analyses were performed using Stata 17.0 (Stata Corp; College Station, TX, USA).

| Search outcomes
A total of 12,101 records were retrieved, and 2426 duplicates were excluded. Subsequently, an additional 9675 records were excluded after reviewing the title and abstract. A total of 44 studies were included in the final meta-analysis, of which 34 were classified as high quality, and 10 were classified as moderate quality (Table S7). The detailed selection process is shown in Figure 1. incidence in 107,527 participants, 25 reported RSV-related hospitalization rates in 62,691,095 participants, nine reported RSV-related inhospital mortality rates in 55,149,680 participants, and five reported RSV-related overall mortality in 31,317,106 participants. Eleven surveys (25.0%) employed active surveillance, 31 (70.5%) employed passive surveillance, and two studies (4.5%) did not mention the surveillance type. Twenty-seven studies (61.4%) were based on national databases, 13 (29.5%) were based on sentinel hospital databases, and four (9.1%) were birth-cohort studies. Two studies (4.5%) used the ILI definition for patient inclusion, and the remaining (95.5%) used the extended ARI definition. Eighteen studies (40.9%) were conducted in high-income countries, 23 (52.3%) in middle-income countries, and three (6.8%) in low-income countries. Overall, participants were aged 0-5 years. A summary of the characteristics of the included studies is shown in Tables S3-S6.

| Synthesis of results
Based on the random-effects model, pooled incidence, hospitalization rate, in-hospital mortality rate, and overall mortality rate among children aged 5 years and younger were 9.0 (95% CI: 7.0-11.0), 1.

| Subgroup analysis
As shown in Table 1 and Figures S1-S4, subgroup analyses of RSVrelated disease incidence, hospitalization rate, in-hospital mortality rate, and overall mortality rate varied according to age, income level, type of surveillance, case definition, and the data source. According to the World Bank classification, the RSV-related disease incidence in high-income countries was higher than that in low-

| Publication bias and sensitivity analysis
The results of the Egger's test did not show any significant publication bias (incidence: t = 2.3, p = 0.5; hospitalization rate: t = 1.6, p = 0.1, in-hospital mortality rate: t = 4.3, p = 0.4; overall mortality rate: t = 2.6, p = 0.1). Details are shown in Figure S5. Sensitivity analyses of RSV-related disease incidence, hospitalization rate, in-hospital mortality rate, and overall mortality rate showed that, after applying the exclusion criteria, there was insignificant change in the estimated acceptance rate, suggesting the robustness of this analysis ( Figure S6).

| DISCUSSION
This meta-analysis sought to comprehensively estimate the RSVrelated disease incidence, hospitalization rate, in-hospital mortality rate, and overall mortality among children aged 5 years and younger.
We aimed to provide basic data that could be used to develop a standardized surveillance system and make recommendations on vaccination of children aged 5 years and younger.
In our study, the pooled RSV-related disease incidence in children aged 5 years and younger was considerably higher than that reported year). 7 The previous article did not specifically report the burden of RSV-ARI in primary care, whereas the studies included in our analysis to estimate the RSV-related incidence were all from outpatients or active community surveillance, which could provide additional data. Furthermore, the higher incidence emphasizes the importance of strengthening surveillance in the community as well as in outpatient clinics.
The pooled RSV-related hospitalization rate was 1.7 per 100 children per year in our study, which was considerably higher than that in  18 On the other hand, the RSV-related in-hospital mortality rate (0.5 per 100 children per year) and overall mortality rate (0.05 per 100 children per year) among children aged 5 years and younger in our study were lower than the rates F I G U R E 2 Synthesis of RSV-associated incidence, hospitalization rate, in-hospital mortality rate and overall mortality rate among children aged 5 years and younger. (A) RSV-related incidence; (B) RSV-related hospitalization rate; (C) RSV-related in-hospital mortality rate; (D) RSV-related overall mortality rate. CI, confidential interval; RSV, respiratory syncytial virus; weights are from random-effects model.
T A B L E 1 Subgroup analysis of RSV-related incidence, hospitalization rate, in-hospital mortality rate, and overall mortality rate among children aged 5 years and younger.  per 100 children per year, respectively). 7 We assumed that an increasing hospitalization rate is not necessarily worrisome and it may reflect increased awareness of diagnosis and sufficient health care resources, which in turn can lead to a reduction in mortality.
To fully understand current studies on RSV-related disease burden among young children, we included studies focused on the whole population and reported corresponding results of 0-5 years old children. Thus, we studied on children ≤5 years rather than <5 years as normally used. Meanwhile, the incidence of RSV-related disease was likely low among 5 years old children, which was also confirmed in our subgroup analysis. Among children ≤5 years, RSV-related disease incidence decreased with increasing age, and the incidence in the 0-  18 We presume that the main reason is that children in low-and middle-income countries may tend to not visit the hospital unless they have severe disease. Li et al. observed that 97% of RSV-attributable deaths occurred in low-and middle-income countries, with the community mortality rate accounting for a higher proportion than the in-hospital mortality rate, 7 confirming that children in low-and middle-income countries may have fewer opportunities to receive healthcare and that awareness of RSV infection diagnosis among clinicians was insufficient (Table S8). We also found that, in-hospital mortality rates were considerably higher in studies with single hospital databases than those in multi-center, long-term, Our study also has some limitations. First, studies published in languages other than English and Chinese were excluded, which may lead to language bias. Second, the included studies had some obvious outliers and considerable heterogeneity owing to the differences in income level, age groups, surveillance types, case ascertainment standards, the diagnostic assays used to identify RSV, and the disparity in access to hospital care across studies. However, we did not exclude those studies considering that they met the inclusion criteria. We calculated the pooled rate and used a random-effects model to synthesize the disease burden, which allows for some outliers and heterogeneity. The sensitivity analyses also confirmed the stability of the result. In addition, the aim of our study was to explore the influencing factors of heterogeneity and to eliminate the lack of comparability between studies in the future. We conducted a supplementary analysis of the studies that constituted the outliers in this section. Third, we only included studies relating to outpatients and community-based surveillance to analyze RSV-related incidence, which may have contributed to a higher incidence rate than that in other studies. However, this could provide a supplementary result for RSV-related incidence in specific primary care settings. Finally, for the publication bias, studies did not conform well to the expected funnel shape, which may be due to the large heterogeneity and small number of the included studies. We further conducted a quantified Egger's test, and the results showed that there was no publication bias (all p > 0.05).

| CONCLUSION
Our research provides an overall estimate of the RSV-related disease burden in children aged 5 years and younger. More attention should be paid to RSV infection in children aged 2 years and younger, who are the target population of the surveillance project. Early detection and treatment can reduce disease severity and RSV-related mortality.
Awareness of RSV case ascertainment should be promoted among healthcare providers in low-and middle-income countries. It is necessary to establish a feasible and standardized RSV surveillance system based on various considerations. Using the definition of extended ARI to determine patient inclusion will increase the sensitivity of case ascertainment. Active community surveillance is the top recommendation, whereas implementing a standard ICD code will be useful in retrospective passive surveillance and hospital-based surveillance.